Vascular Biology Program and Department of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
N Engl J Med. 2010 Mar 18;362(11):1005-13. doi: 10.1056/NEJMoa0903036.
Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells.
We tested hemangioma-derived stem cells for vasculogenic activity in vivo after implantation into immune-deficient (nude) mice. We studied dexamethasone treatment of both the cells before implantation and the mice after implantation. We also tested hemangioma-derived stem cells for expression of vascular endothelial growth factor A (VEGF-A) in vitro and studied the inhibition of VEGF-A expression, using short hairpin RNA (shRNA) in vivo and in vitro.
Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. Pretreatment of hemangioma-derived stem cells in vitro before implantation also inhibited vasculogenesis. Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. Silencing VEGF-A in hemangioma-derived stem cells reduced vasculogenesis in vivo. VEGF-A was detected in hemangioma specimens in the proliferating phase but not in the involuting phase and was shown by immunostaining to reside outside of vessels. Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1.
In a murine model, dexamethasone inhibited the vasculogenic potential of stem cells derived from human infantile hemangioma. The corticosteroid also inhibited the expression of VEGF-A by hemangioma-derived stem cells, and silencing of VEGF-A expression in these cells inhibited vasculogenesis in vivo.
皮质类固醇常用于治疗婴儿血管瘤，但这种治疗方法的作用机制尚不清楚。我们在之前描述的婴儿血管瘤体内模型和培养的血管瘤衍生细胞中研究了皮质类固醇的作用。
我们将血管生成活性检测到的血管瘤衍生干细胞植入免疫缺陷（裸）小鼠体内，观察其在体内的作用。我们研究了在植入前对细胞和植入后对小鼠进行地塞米松治疗的效果。我们还检测了体外培养的血管瘤衍生干细胞中血管内皮生长因子 A（VEGF-A）的表达，并在体内和体外使用短发夹 RNA（shRNA）研究了 VEGF-A 表达的抑制作用。
在小鼠模型中，全身性给予地塞米松治疗导致肿瘤血管生成呈剂量依赖性抑制。体外植入前对血管瘤衍生干细胞进行预处理也抑制了血管生成。地塞米松抑制了血管瘤衍生干细胞体外产生 VEGF-A，但不抑制血管瘤衍生内皮细胞或人脐静脉内皮细胞产生 VEGF-A。沉默血管瘤衍生干细胞中的 VEGF-A 减少了体内血管生成。在增殖期的血管瘤标本中检测到 VEGF-A，但在消退期的标本中未检测到，免疫组化染色显示 VEGF-A 位于血管外。皮质类固醇治疗抑制了血管瘤衍生干细胞中的其他促血管生成因子，包括尿激酶型纤溶酶原激活物受体、白细胞介素 6、单核细胞趋化蛋白 1 和基质金属蛋白酶 1。
在小鼠模型中，地塞米松抑制了来源于人类婴儿血管瘤的干细胞的血管生成潜力。皮质类固醇还抑制了血管瘤衍生干细胞中 VEGF-A 的表达，沉默这些细胞中的 VEGF-A 表达抑制了体内血管生成。
